Project Summary/Abstract Intervertebral disc injury through trauma, exposure to vibrational loading, or mechanical overload, and the resulting disc degeneration in response to these insults over time are tremendous problems affecting the active and veteran military population. As high as 44% of U.S. Gulf War veterans report low back pain only 2 to 5 years following service, an incidence rate 14% higher than non-active duty veterans and a rate nearly twice that of the general US population. Despite its link with pain, there are no treatments that stop the progression of disc degeneration. The objective of this proposal is to investigate the mechanisms of and potential restorative therapies for intervertebral disc degeneration utilizing an in vitro nucleus pulposus (NP) model and an in vivo small animal model. Disc degeneration is complex and multifactorial. Clinical studies, animal models, and in vitro experiments have demonstrated inflammatory cytokines play a role in degeneration. In particular, inflammatory cytokines interleukin-12 (IL12) and tumor necrosis factor 1 (TNF1) are present in degenerated human discs. Both the in vitro and in vivo models proposed here will elucidate the mediators and mechanisms involved in progressive degeneration and act as platforms to evaluate two agents that counteract these inflammatory cytokines, IL1 receptor antagonist (IL1RA) and soluble TNF receptor 1(sTNFR1), which have strong therapeutic potential. We will test these potential therapies in the following Aims: Aim 1: Investigate a potential therapy using an in vitro NP model Aim 2: Use biodegradable polymeric microspheres to deliver therapeutic agents Aim 3: Evaluate therapeutic agents in an in vivo model of disc degeneration If successful, future work will study these agents in naturally occurring models of degeneration and in translational large animal models. Other potential therapeutic agents can be developed and tested using the model systems developed in this study. This work will impact treatment for a significant proportion of the population, including military active duty and veteran, who suffer with disc degeneration and back pain.